This project is a continuation of a project in the original cycle of our PPG two decades ago. The concept is to apply the power of mouse genetics to understand, in vivo, the complex physiologic, cellular and molecular interactions that contribute to cardiovascular disease and the metabolic syndrome. During the current grant, we positionally cloned a gene in mouse that results in a combined hyperlipidemic phenotype. The gene proved to correspond to thioredoxin interacting protein (Txnip), a poorly understood protein that binds to and inactivates thioredoxin. Our recent studies and those of other laboratories have now implicated Txnip in fundamental regulation of both lipid and glucose metabolism. We will now examine the mechanisms involved using our mouse model. Another protein that we identified in genetic studies in mice is apolipoprotein All (apoAII). We have shown that the levels of this protein, ranging from null (apoAII knockout) to a few mg/dl (strain SM) to approximately 20 mg/dl (strain C57BL/6) to approximately 30 mg/dl (strain BALB/c) to approximately 100 mg/dl (apoAII transgenic) have;a continuous, significant impact on insulin resistance, triglyceride levels, body fat, atherosclerosis and inflammatory properties of HDL. We now propose to further pursue the causal interactions involved. The third aim is to positionally clone a novel gene in mouse that contributes to combined hyperlipidemia and atherosclerosis. The last aim is to study in mouse a gene that was positionally cloned in the current grant in studies of Finnish familial combined hyperlipidemic pedigrees. The gene, USF1, will be examined in knockout and transgenic mouse models on a variety of backgrounds. Project I will interact with each of the other projects and with all the cores.